The ability to predict globular protein tertiary structure from the primary sequence along with the elucidation of the folding mechanism are very tantalizing problems in molecular biology, whose solution would have broad practical consequences in protein engineering. The overall objectives are to finish the development of algorithms capable of providing not only the tertiary structure, but also the folding pathway and to apply these algorithms to real proteins. For qualitative insights, as well as to establish the sensitivity of the conclusions to local details, both idealized and real proteins will be examined. Highly efficient, on lattice Monte Carlo (MC) dynamics will be used to elucidate the general folding/unfolding pathways and to provide a 2-3 A0 resolution, native alpha-carbon backbone plus sidechain conformation. The on-lattice, native conformation will then be pulled off lattice, all of the atoms inserted and then further refined using off-lattice MC, or molecular dynamics (MD). Employing umbrella sampling with a reaction coordinate obtained from on-lattice MC, the rates of folding and unfolding will be obtained via MD or off-lattice MC. This will permit comparison of more realistic folding rates with those obtained using onlattice MC. Specifically, this proposal will develop: (1) a more realistic sidechain description for on-lattice folding; (2) parameter sets describing the local conformational preferences of residues; (3) further refinements of algorithms that pull the folded chain off-lattice, insert all the atoms, and refine the folded conformation; (4) the role of short vs. long-range interactions In folding will be explored; (5) the nature of early and late folding intermediates will be examined both in vitro and under highly idealized in vivo conditions.